HAIFA, Israel (Press Release) — The connection between the body and the brain has preoccupied philosophers and researchers for thousands of years. A new study at the University of Haifa has identified a neural circuit that enables the brain to regulate the activity of the immune system through learning processes similar to associative learning.
The findings demonstrate that the brain and the immune system collaborate to prepare for future challenges and reveal how they “learn” to activate the immune system based solely on sensory information and brain activity. This process involves the “representation” of the immune system in the brain and the integration of this information with sensory inputs, such as taste.
The study was led by Dr. Haneen Kayyal, Federica Cruciani, and Dr. Sailendrakumar Kolatt Chandran, in collaboration with Prof. Amiram Ariel (Haifa University) and Prof. Asya Rolls from the Technion. It was conducted at the laboratory for Research of Molecular and Cellular Mechanisms Underlying Learning and Memory, headed by Prof. Kobi Rosenblum, at the University of Haifa.
Prof. Rosenblum explains: “We knew that the immune system can sense cells in the body that are behaving abnormally or detect bacteria or viruses that have invaded the body. It can also learn and act decisively and rapidly against invaders it has encountered in the past. Until now, however, researchers believed that the immune system could not connect the information it holds with sensory information stored in the brain – a capability that would provide any animal with a significant evolutionary advantage. Through the senses, the brain constantly samples the environment. Accordingly, we asked whether the brain and the immune system can share information to improve a person’s health. If so, where does the encounter take place between the memories stored in the brain and the immune system?”
In the study, published in the prestigious journal Nature Neuroscience, the researchers drew on three key existing findings. The first, from a study conducted 70 years ago, demonstrated that it is possible to create an association between a particular taste and the activation or suppression of the immune system. Following this associative learning -which is similar to other forms of learning- when a person or animal is exposed to the same taste weeks or months later, their immune response mirrors that at the time of the initial learning, even though no direct factor is acting on the immune system. This phenomenon, known as the conditioned immune response, is considered a primitive explanation for the placebo effect, where an ostensibly inert and inactive substance improves a person’s health condition.
The impact of the brain and learning processes on our health is tied to the broader body-brain connection. The researchers identified a protocol in which a single pairing of a new taste (saccharin) with the injection of a substance derived from the bacterial capsule (LPS, which the immune system recognized as a bacteria and mounts a response against) causes a similar immune reaction even days later. This occurs solely because the mice in the experiment had previously consumed the saccharin.
To understand how and where in the brain the learning for this conditioned immune response occurs, the researchers relied on previous laboratory studies. These studies demonstrated that the coding and evaluation of new tastes –whether they are perceived as pleasant, novel, or aversive- take place in the inner section of the cortex known as the insula. Another study revealed that coding for representing an immune response takes place in the rear section of the insula. Based on these findings the researchers hypothesized that the coding or cerebral representation of the conditioned immune response would involve a connection between the front and rear sections of the insula.
In order to test this hypothesis, the researchers first replicated the conditioned immune response in mice. They demonstrated that that a single pairing of consuming a novel taste (saccharin) with an injection of LPS into the abdominal cavity caused the mice to develop an aversion to the taste (retrieval of the memory of altered taste evaluation). Additionally, the presentation of the same taste after learning triggered an immune response (retrieval of the memory of the immune response).
The researchers next showed that there is a clear neural connection between the peripheral nervous system in the and the insula (including both the rear and front sections), enabling the passage of information.
In order to investigate whether there is a correlation between the activity of the neural cells that transmit information between the front and rear of the insula (two-way communication), the researchers examined whether these connecting cells were activated following retrieval of the conditioned immune response and whether their electrical properties changed. .
The researchers found that there was no change in the majority of nerve cells in the front and rear sections of the insula following the retrieval of the memory of immune conditioning. However, clear activation was observed in a specific group of cells that connects the front and rear sections. It is important to note that this group of connecting cells represents a small and specialized subset of the total nerve cells in the insula.
After identifying a correlation between the activity of the nerve cells that connect the front and rear sections of the insula and conditioned immune learning, the researchers examined the hypothesis that this activity is also indispensable for retrieving the memory of immune association. To do this, they suppressed the pathways of these nerve cells (in both directions) during the retrieval of the conditioned immune response. They found that disrupting these pathways significantly impacted the retrieval of the immune response. In other words, these neural pathways play an essential role in transmitting information between the brain and the immune system – a key example of functional body-brain communication.
Conversely, when examining the retrieval of the behavioral memory of taste revulsion following the association, the researchers found that only the rear-to-front pathway, and not the front-to-rear pathway, is essential for retrieving the behavioral memory.
The researchers emphasized that this is the first -time science has identified the specific nerve cells and pathways in mammals that enable integrating sensory information with information from the immune system. This basic understanding opens new therapeutic possibilities for a variety of diseases. Many illnesses arise from the impairments in the immune system’s ability to respond to threats, leading to either to overactive or insufficient responses. This study suggests new therapeutic directions in which the regulation of behavior, brain activity, and the immune system function are coordinated to optimize disease treatment.
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Preceding provided by the University of Haifa.